Sphingosine 1-phosphate (SIP) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family, namely S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly EDG1, EDG5, EDG3, EDGE and EDG8). The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Gα) subunits and beta-gamma (Gβγ) dimers. These receptors share 50-55% amino acid sequence identity and cluster with three other structurally related lysophosphatidic acid (LPA) receptors, namely LPA1, LPA2, and LPA3 (formerly EDG2, EDG4 and EDG7).
The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the immunomodulating agent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol), that following phosphorylation, is an agonist at 4 of 5 S1P receptors (i.e., S1P1, S1P3, S1P4, and S1P5), revealed that affecting SIP receptor activity influences lymphocyte trafficking. In particular, S1P type 4 receptors (S1P4) are expressed mainly in leukocytes, and specifically S1P4 mediates immunosuppressive effects of S1P by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10. See, for example, Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which is incorporated by reference in its entirety.
S1P type 5 receptors (S1P5) are predominantly expressed in white matter tracts, oligodendrocyte precursor cells (OPCs), and remain expressed in mature myelinating oligodendrocytes. In the central nervous system, OPCs arise in restricted periventricular germinal and migrate to developing white matter where they differentiate and form myelin sheaths around axons that insulate them and enhance conduction velocity of electrical impulses. Binding of S1P to S1P5 receptors has been shown to be a negative regulator of OPC motility through a Rho kinase-dependent pathway involving phosphorylation of collapsing response-mediated protein (CRMP2). In mature oligodendrocytes, however, binding of S1P to S1P5 receptors results in increased cell survival, mediated through an Akt signaling pathway. (Novgorodov, A. et al., (2007) FASEB J, 21: 1503-1514 and Jaillard, et al., the Journal of Neuroscience (2005), 25(6):1459-1469, both of which are incorporated by reference in their entirety). This data suggests that S1P5 receptors are involved in regulating myelination.
A number of diseases or disorders involve demyelination of the central or peripheral nervous system which can occur for a number of reasons such as immune dysfunction as in multiple sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, stroke, acute ischemic optic neuropathy, or other ischemia, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g. in Bell's palsy)), post radiation injury, and central pontine myelolysis (CPM); inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, and nerve damage due to pernicious anemia; viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, or tabes dorsalis due to untreated syphilis; toxic exposure due to chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease), chemotherapy, or exposure to chemicals such as organophosphates; or dietary deficiencies such as vitamin B12 deficiency, vitamin E deficiency and copper deficiency. Other demyelination disorders may have unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease and Bell's palsy. One practically successful approach to treating demyelination disorders which are caused by autoimmune dysfunction has been to attempt to limit the extent of demyelination by treating the patient with immunoregulatory drugs. However, typically this approach has merely postponed but not avoided the onset of disability in these patients. Patients with demyelination due to other causes have even fewer treatment options. Therefore, the need exists to develop new treatments for patients with demyelination diseases or disorders.
Moreover, altered sphingolipid metabolism has been shown to play a role in cognitive and neurodegenerative diseases. It has been observed that the brains of patients with Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and acquired immunodeficiency syndrome (AIDS) dementia have been shown to have elevated ceramide and sphingosine and low S1P compared to cognitively normal individuals. In patients with Alzheimer's disease, it has been shown that genes responsible for ceramide synthesis and S1P degradation are upregulated while genes responsible for S1P synthesis remain the same as cognitively normal individuals (Mielke, M. M. and Lyketsos, C. G., Neuromolecular Med. (2010), 12(4):331-340). This data suggests that high ceramide and low S1P are the hallmarks of neurodegenerative disease.
While ceramide has been shown to be pro-apoptotic, the binding of S1P to S1P receptors has been linked to resistance to apoptosis, increased cell migration and division, and oligodendrocyte differentiation and survival. Compounds which could either shift the balance of ceramide/S1P in favor of S1P-mediated survival and away from ceramide-mediated cell death or which could mimic the activity of S1P in the brain are expected to be of benefit in treating neurodegenerative and cognitive disorders.